scholarly journals Tumor Necrosis Factor-α Promotes Survival of Opossum Kidney Cells via Cdc42-induced Phospholipase C-γ1 Activation and Actin Filament Redistribution

2004 ◽  
Vol 15 (3) ◽  
pp. 1273-1286 ◽  
Author(s):  
Evangelia A. Papakonstanti ◽  
Christos Stournaras
Keyword(s):  
Tumor Necrosis ◽  
Caspase 3 ◽  
Nuclear Factor Κb ◽  
Kidney Cells ◽  
Nuclear Factor ◽  
Signaling Mechanism ◽  
Opossum Kidney ◽  
Opossum Kidney Cells ◽  
Tnf Α ◽  
Necrosis Factor

Although the renal proximal tubular epithelial cells are targeted in a variety of inflammatory diseases of the kidney, the signaling mechanism by which tumor necrosis factor (TNF)-α exerts its effects in these cells remains unclear. Here, we report that TNF-α elicits antiapoptotic effects in opossum kidney cells and that this response is mediated via actin redistribution through a novel signaling mechanism. More specifically, we show that TNF-α prevents apoptosis by inhibiting the activity of caspase-3 and this effect depends on actin polymerization state and nuclear factor-κB activity. We also demonstrate that the signaling cascade triggered by TNF-α is governed by the phosphatidylinositol-3 kinase, Cdc42/Rac1, and phospholipase (PLC)-γ1. In this signaling cascade, Cdc42 was found to be selectively essential for PLC-γ1 activation, whereas phosphatidylinositol-3,4,5-triphosphate alone is not sufficient to activate the phospholipase. Moreover, PLC-γ1 was found to associate in vivo with the small GTPase(s). Interestingly, PLC-γ1 was observed to associate with constitutively active (CA) Cdc42V12, but not with CA Rac1V12, whereas no interaction was detected with Cdc42(T17N). The inactive Cdc42(T17N) and the PLC-γ1 inhibitor U73122 prevented actin redistribution and depolymerization, confirming that both signaling molecules are responsible for the reorganization of actin. Additionally, the actin filament stabilizer phallacidin potently blocked the nuclear translocation of nuclear factor-κB and its binding activity, resulting in abrogation of the TNF-α-induced inhibition of caspase-3. To conclude, our findings suggest that actin may play a pivotal role in the response of opossum kidney cells to TNF-α and implicate Cdc42 in directly regulating PLC-γ1 activity.

Activated Protein C Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production by Inhibiting Activation of both Nuclear Factor-κB and Activator Protein-1 in Human Monocytes

2002 ◽  
Vol 88 (08) ◽  
pp. 267-273 ◽  
Author(s):  
Mehtap Yuksel ◽  
Mitsuhiro Uchiba ◽  
Seikoh Horiuchi ◽  
Hiroaki Okabe ◽  
Kenji Okajima
Keyword(s):  
Protein C ◽  
Tumor Necrosis ◽  
Activated Protein C ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Tnf Α ◽  
Target Sites ◽  
Factor Α ◽  
Necrosis Factor

SummaryActivated protein C (APC), an important natural anticoagulant, inhibits tumor necrosis factor-α (TNF-α) production and attenuates various deleterious events induced by lipopolysaccharide (LPS), contributing thereby to a significant reduction of mortality in patients with severe sepsis. In this study, we investigated the mechanism(s) by which APC inhibits TNF-α production by LPS-stimulated human monocytes in vitro. Although APC inhibited LPS-induced TNF-α production in a concentration-dependent fashion, diisopropyl fluorophosphate-treated APC, an active-site-blocked APC, had no effect. APC inhibited both the binding of nuclear factor-κB (NF-κB) to target sites and the degradation of IκBα. APC also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. These observations strongly suggest that APC inhibited LPS-induced TNF-α production by inhibiting the activation of both NF-κB and AP-1 and that the inhibitory activity of APC might depend on its serine protease activity. These results would at least partly explain the mechanism(s) by which APC reduces the tissue injury seen in animal models of sepsis and in patients with sepsis.

Monoammonium glycyrrhizate suppresses tumor necrosis factor-α induced chemokine production in HMEC-1 cells, possibly by blocking the translocation of nuclear factor-κB into the nucleus

2014 ◽  
Vol 92 (10) ◽  
pp. 859-865 ◽  
Author(s):  
Na Cao ◽  
Tao Chen ◽  
Zai-pei Guo ◽  
Sha Qin ◽  
Meng-meng Li
Keyword(s):  
Tumor Necrosis ◽  
Skin Diseases ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Inflammatory Skin Diseases ◽  
Chemokine Production ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Necrosis Factor

Monoammonim glycyrrhizate (MAG) derived from licorice has been shown to have anti-inflammatory properties. Chemokines are vital inflammatory mediators that are involved with endothelial damage from leukocyte infiltrates in various inflammatory skin diseases. In this study, we investigated the anti-inflammatory effects and mechanisms of MAG on tumor necrosis factor-α (TNF-α) induced chemokine production in a human dermal microvascular endothelial cell line (HMEC-1). HMEC-1 cells were treated with TNF-α, with or without MAG. The results showed that MAG suppressed TNF-α-induced chemokine (including CXCL8, CX3CL1, and CXCL16) mRNA expression in HMEC-1 cells, in a dose-dependent manner, and reduced the secretion of these chemokines in culture supernatant. Moreover, endothelial activation in the presence of MAG blocked the chemotactic activities of TNF-α-stimulated HMEC-1 cell supernatant on the migration of primary neutrophils and primary monocytes. In addition, Western blot and immunofluorescence data revealed that MAG inhibited nuclear translocation of nuclear factor-κB p65 (NF-κB p65). It is the first report to demonstrate that MAG suppresses TNF-α-induced chemokine production in HMEC-1 cells, and that the mechanism may be inhibiting the translocation of NF-κB p65 into the nucleus to prevent the starting of inflammatory signaling pathway. Our results revealed that MAG is a potential anti-inflammatory agent capable of improving inflammatory skin diseases.

I. TNF-induced liver injury

1998 ◽  
Vol 275 (3) ◽  
pp. G387-G392 ◽  
Author(s):  
Cynthia A. Bradham ◽  
Jörg Plümpe ◽  
Michael P. Manns ◽  
David A. Brenner ◽  
Christian Trautwein
Keyword(s):  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Nuclear Factor Κb ◽  
Hepatocyte Proliferation ◽  
Nuclear Factor ◽  
Normal Hepatocyte ◽  
Tnf Α ◽  
Factor Α ◽  
Transcription Factor Nuclear Factor ◽  
Necrosis Factor

Tumor necrosis factor-α (TNF-α) functions as a two-edged sword in the liver. TNF-α is required for normal hepatocyte proliferation during liver regeneration. It functions both as a comitogen and to induce the transcription factor nuclear factor-κB, which has antiapoptotic effects. On the other hand, TNF-α is the mediator of hepatotoxicity in many animal models, including those involving the toxins concanavalin A and lipopolysaccharide. TNF-α has also been implicated as an important pathogenic mediator in patients with alcoholic liver disease and viral hepatitis.

Regulation of Fas (CD95)-induced apoptosis by nuclear factor-κB and tumor necrosis factor-α in macrophages

2002 ◽  
Vol 283 (3) ◽  
pp. C831-C838 ◽  
Author(s):  
Bin Lu ◽  
Liying Wang ◽  
Djordje Medan ◽  
David Toledo ◽  
Chuanshu Huang ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Necrosis Factor

The APO-1/Fas ligand (FasL) and tumor necrosis factor-α (TNF-α) are two functionally related molecules that induce apoptosis of susceptible cells. Although the two molecules have been reported to induce apoptosis via distinct signaling pathways, we have shown that FasL can also upregulate the expression of TNF-α, raising the possibility that TNF-α may be involved in FasL-induced apoptosis. Because TNF-α gene expression is under the control of nuclear factor-κB (NF-κB), we investigated whether FasL can induce NF-κB activation and whether such activation plays a role in FasL-mediated cell death in macrophages. Gene transfection studies using NF-κB-dependent reporter plasmid showed that FasL did activate NF-κB promoter activity. Gel shift studies also revealed that FasL mobilized the p50/p65 heterodimeric form of NF-κB. Inhibition of NF-κB by a specific NF-κB inhibitor, caffeic acid phenylethyl ester, or by dominant expression of the NF-κB inhibitory subunit IκB caused an increase in FasL-induced apoptosis and a reduction in TNF-α expression. However, neutralization of TNF-α by specific anti-TNF-α antibody had no effect on FasL-induced apoptosis. These results indicate that FasL-mediated cell death in macrophages is regulated through NF-κB and is independent of TNF-α activation, suggesting the antiapoptotic role of NF-κB and a separate death signaling pathway mediated by FasL.

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